Aminopyrimidines useful as inhibitors of protein kinases

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

This application is a continuation of PCT/US07/088,058 filed Dec. 19,2007 which claims the benefit of U.S. Provisional Application No.60/875,729 filed Dec. 19, 2006 and U.S. Provisional Application No.60/953,027 filed Jul. 31, 2007.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofprotein kinases. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders. Theinvention also provides processes for preparing the compounds of theinvention.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology 2000, 7, 793-803; and Kim andKimmel, Curr. Opinion Genetics Dev., 2000 10, 508-514]. GSK-3 has beenimplicated in various diseases, disorders, and conditions includingdiabetes, Alzheimer's disease, CNS diseases such as bipolar disorder,schizophrenia, cerebral stroke, Huntington's and other neurodegenerativediseases, leukocytopenia and cardiomyocyte hypertrophy [PCT ApplicationNos.: WO 99/65897 and WO 00/38675; and Haq et al., J. Cell Biol. 2000,151, 117-130]. These diseases, disorders, and conditions are associatedwith the abnormal operation of certain cell signaling pathways in whichGSK-3 plays a role. GSK-3 has been found to phosphorylate and modulatethe activity of a number of regulatory proteins. These proteins includeglycogen synthase, which is the rate limiting enzyme necessary forglycogen synthesis, the microtubule associated protein Tau, the genetranscription factor β-catenin, the translation initiation factor e1F2B,as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-myc,c-myb, CREB, and CEPBA. These diverse protein targets implicate GSK-3 inmany aspects of cellular metabolism, proliferation, differentiation, anddevelopment.

In a GSK-3 mediated pathway that is relevant for the treatment of typeII diabetes, insulin-induced signaling leads to cellular glucose uptakeand glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS1996, 93, 8455-8459; Cross et al., Biochem. J. 1994, 303, 21-26); Cohen,Biochem. Soc. Trans. 1993, 21, 555-567; and Massillon et al., Biochem J.1994, 299, 123-128]. However, in a diabetic patient, where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long-term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[see, PCT Application: WO 00/38675]. Therapeutic inhibitors of GSK-3 aretherefore potentially useful for treating diabetic patients sufferingfrom an impaired response to insulin.

GSK-3 activity is associated with Alzheimer's disease. The hallmarks ofthis disease are the extracellular plaques formed by aggregatedβ-amyloid peptides and the formation of intracellular neurofibrillarytangles via the tau protein.

It has been shown that GSK-3 inhibition reduces amyloid-β peptides in ananimal model of Alzheimer's disease. See pages 435, 438. Phiel et. al.,Nature 423, 435-439 (2003). Mice over-expressing amyloid precursorprotein (APP) treated with lithium (a GSK-3α inhibitor) over athree-week period showed over a 50% decrease in amyloid-β peptide tissuelevels.

The neurofibrillary tangles contain hyperphosphorylated Tau protein, inwhich Tau is phosphorylated on abnormal sites. GSK-3 is known tophosphorylate these abnormal sites in cell and animal models.Conditional transgenic mice that over-express GSK-3 develop aspects ofAD including tau hyperphosphorylation, neuronal apoptosis and spatiallearning deficit. Turning off GSK-3 in these mice restores normalbehavior, reduces Tau hyperphosphorylation and neuronal apoptosis.(Engel T et al., J Neuro Sci, 2006, 26, 5083-5090 and Lucas et al, EMBOJ, 2001, 20, 27-39) Inhibitors of GSK-3 have also been shown to preventhyperphosphorylation of Tau in cells [Lovestone et al., Current Biology1994, 4, 1077-86; and Brownlees et al., Neuroreport 1997, 8, 3251-55].

GSK-3 as a target for psychosis and mood disorders, such asschizophrenia and bipolar disease, respectively, have been reported inthe literature. AKT haplotype deficiency was identified in a subset ofschizophrenic patients which correlated with increased GSK-3 activity. Asingle allele knockout of GSK-3β resulted in attenuated hyperactivity inresponse to amphetamine in a behavior model of mania.

Several antipsychotic drugs and mood stabilizers used to treat bothschizophrenic and bipolar patients have been shown to inhibit GSK-3(Emamian et al, Nat Genet, 2004, 36, 131-137; Obrien et al, J Neurosci,2004, 24, 6791-6798; Beaulieu et al, PNAS, 2004, 101, 5099-5104; Li etal Int J Neuropsychopharmacol, 2006, pp 1-13; Gould T D, Expert OpinTher Targets, 2006, 10, 377-392). Furthermore, a recent patentpublication, US 2004/0039007, describes GSK-3 inhibitors that showanti-schizophrenic and anxiolytic effects in relevant mouse behaviormodels.

GSK-3 activity is associated with stroke. Wang et al. showed that IGF-1(insulin growth factor-1), a known GSK-3 inhibitor, reduced infarct sizein rat brains after transient middle cerebral artery occlusion (MCAO), amodel for stroke in rats. [Wang et al., Brain Res 2000, 859, 381-5;Sasaki et al., Neurol Res 2001, 23, 588-92; Hashimoto et al., J. Biol.Chem 2002, 277, 32985-32991]. US 2004/0039007 describes the effect ofGSK-3 inhibitors in MCAO, a stroke model in rats. These GSK-3 inhibitorssignificantly reduced striatal ischemic damage and reduce edemaformation in rats. Additionally, the rats “demonstrated markedimprovement in neurological function over the time course of theexperiment.”

Inhibition of GSK-3 activity has been linked to stem cell proliferation,differentiation and neuronal plasticity Inhibitors of GSK-3 have beenshown to sustain self-renewal of embryonic stem cells, promote neuron,beta-cell, myeloid and osteoblast differentiation. (Sato et al, NatureMedicine 10, 55-63, 2004; Ding et al PNAS 100, 7632-37, 2003; Branco etal J Cell Science 117, 5731-37, 2004; Trowbridge et al, Nature Medicine12, 89-98, 2006; Mussmann et al, JBC (Epub ahead of print) 2007;Kulkarni et al Journal of Bone and Mineral Res. 21, 910-920, 2006) Withrespect to neuronal plasticity, inhibition of GSK-3 has been shown to beimportant for regulating polarity, long-term potentiation (LTP) andneurite/axon growth (Hooper et al European J of Neuroscience 25, 81-86,2007; Kim et al, Neuron 52, 981-996, 2006; Jiang et al Cell 120,123-135, 2005;). Taken all together, GSK-3 small-molecule inhibitorshave the potential to act as chemomodulators of cell differentiation andplasticity which has implications for many types of degenerativeconditions such as Neurodegenerative diseases (Stroke, Alzheimer,Parkinson, Huntington, ALS and Multiple Sclerosis), Leukocytopenia,Diabetes and Osteoporosis.

Accordingly, there is a great need to develop compounds useful asinhibitors of protein kinases. In particular, it would be desirable todevelop compounds that are useful as inhibitors of GSK-3, particularlygiven the inadequate treatments currently available for the majority ofthe disorders implicated in their activation.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

wherein the variables are as defined herein.

The present invention also provides processes for preparing thesecompounds, compositions, pharmaceutical compositions, and methods ofusing such compounds and compositions for inhibiting protein kinases.These compounds are particularly useful as GSK-3 inhibitors.

These compounds and pharmaceutically acceptable compositions thereof areuseful for treating or preventing a variety of diseases, disorders orconditions, including, but not limited to, an autoimmune, inflammatory,proliferative, or hyperproliferative disease, a neurodegenerativedisease, or an immunologically-mediated disease.

The compounds provided by this invention are also useful for the studyof kinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases; andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ht is

-   -   Ring D is a 4-7 membered monocyclic ring or 8-10 membered        bicyclic ring selected from a heterocyclyl or a carbocyclyl        ring; said heterocyclyl ring having 1-4 ring heteroatoms        selected from nitrogen, oxygen or sulfur, wherein each        substitutable ring carbon of Ring D is independently substituted        with oxo or —R⁵, and any substitutable ring nitrogen is        independently substituted with —R⁴;    -   X is sulfur, oxygen, or NR^(2′);    -   Y is nitrogen or CR²;    -   Z¹ and Z² are each independently N or CR⁹; provided that at        least one of Z¹ or Z² is N;    -   R^(X) is T¹-R³;    -   R^(Y) is T²-R¹⁰;    -   R² and R^(2′) are independently selected from —R or -T³-W—R⁶; or        R² and R^(2′) are taken together with their intervening atoms to        form a fused, 5-8 membered, unsaturated or partially        unsaturated, ring having 0-3 ring heteroatoms selected from        nitrogen, oxygen, or sulfur, wherein each substitutable carbon        on said fused ring formed by R² and R^(2′) is substituted with        halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and any substitutable        nitrogen on said ring formed by R² and R^(2′) is substituted        with R⁴;    -   each T, T¹ and T³ is independently a bond or a C₁₋₄ alkylidene        chain;    -   T² is independently a bond or a C₁₋₄ alkylidene chain wherein up        to three methylene units of the alkylidene chain are optionally        replaced by —O—, —C(═O)—, —S(O)—, —S(O)₂—, —S—, or —N(R⁴)—;    -   R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,        —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,        —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂R″, —N(R⁴)N(R⁴)₂,        —C(═NH)N(R⁴)₂, —C(═NH)—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,        —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;    -   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂        (optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷,        or two R⁴ on the same nitrogen are taken together to form a 3-8        membered heterocyclyl or heteroaryl ring;    -   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,        —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,        —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂R″,        —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,        —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;    -   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,        —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,        —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—,        —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,        —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—,        —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,        —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;    -   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,        —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O)—,        —C(R⁶)₂OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—,        —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,        —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;    -   each R⁶ is independently selected from hydrogen or C₁₋₄        aliphatic group optionally substituted with 0-3 J⁶; or two R⁶        groups on the same nitrogen atom are taken together with the        nitrogen atom to form a 4-6 membered heterocyclyl or heteroaryl        ring, wherein said heterocyclyl or heteroaryl ring is optionally        substituted with 0-4 J⁶;    -   each R⁷ is independently selected from hydrogen or R″; or two R⁷        on the same nitrogen are taken together with the nitrogen to        form a 4-8 membered heterocyclyl or heteroaryl ring, wherein        said heterocyclyl or heteroaryl ring is optionally substituted        with 0-4 J⁷;    -   each R⁹ is —R′, -halo, —OR′, —C(═O)R′, —CO₂R′, —COCOR′,        COCH₂COR′, —NO₂, —CN, —S(O)R′, —S(O)₂R′, —SR′, —N(R′)₂,        —CON(R′)₂, —SO₂N(R′)₂, —OC(═O)R′, —N(R′)COR′, —N(R′)CO₂(C₁₋₆        aliphatic), —N(R′)N(R′)₂, —N(R′)CON(R′)₂, —N(R′)SO₂N(R′)₂,        —N(R′)SO₂R′, —OC(═O)N(R′)₂, ═NN(R′)₂, ═N—OR′, or ═O;    -   each R¹⁰ is a 4-membered heterocyclic ring containing 1-2        heteroatoms selected from O, NR¹¹, and S; each R¹⁰ is optionally        substituted with 0-3 occurrences of J;    -   each R¹¹, is —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆        aliphatic), —CON(R⁷)₂, or —SO₂R⁷;    -   each R is independently selected from hydrogen or an optionally        substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a        heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring        having 4-10 ring atoms; each R is optionally substituted with        0-5 R⁹;    -   each R′ is independently hydrogen or a C₁₋₆ aliphatic group        optionally substituted with 0-4 J′; or two R′, together with the        atom(s) to which they are attached, form a 3-6 membered        carbocyclyl or heterocyclyl wherein said carbocyclyl or        heterocyclyl is optionally substituted with 0-4 J′;    -   each R″ is independently C₁₋₆ aliphatic optionally substituted        with 0-4 J″;    -   each J′ and J″ is independently NH₂, NH(C₁₋₄aliphatic),        N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic),        NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or        haloC₁₋₄aliphatic;    -   each J, J⁶, and J⁸ is independently -halo, —OR, oxo, C₁₋₆        aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R,        —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R,        —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, ═NN(R⁴)₂,        ═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or        —OC(═O)N(R⁷)₂;    -   each J⁷ is independently -halo, —OR, oxo, C₁₋₆ aliphatic,        —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R,        —SR, —N(R¹²)₂, —CON(R¹²)₂, —SO₂N(R¹²)₂, —OC(═O)R, —N(R¹²)COR,        —N(R¹²)CO₂(C₁₋₆ aliphatic), —N(R¹²)N(R²)₂, ═NN(R¹²)₂, ═N—OR,        —N(R¹²)CON(R¹²)₂, —N(R¹²)SO₂N(R¹²)₂, —N(R¹²)SO₂R, or        —OC(═O)N(R¹²)₂; or    -   2 J groups, 2 J⁶ groups, 2 J⁷ groups, or 2 J⁸ groups, on the        same atom or on different atoms, together with the atom(s) to        which they are bound, form a 3-8 membered saturated, partially        saturated, or unsaturated ring having 0-2 heteroatoms selected        from O, N, or S;    -   R¹² is independently selected from hydrogen or R″; or two R¹² on        the same nitrogen are taken together with the nitrogen to form a        4-8 membered heterocyclyl or heteroaryl ring, wherein said        heterocyclyl or heteroaryl ring is optionally substituted with        0-4 J″.

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, a specified number range of atoms includes anyinteger therein. For example, a group having from 1-4 atoms could have1, 2, 3, or 4 atoms.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, recovery, purification, and use for one or moreof the purposes disclosed herein. In some embodiments, a stable compoundor chemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or less, in the absence of moistureor other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or cyclic, branched or unbranched,substituted or unsubstituted hydrocarbon chain that is completelysaturated or that contains one or more units of unsaturation that has asingle point of attachment to the rest of the molecule. Unless otherwisespecified, aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, or alkynyl groups. Specific examples include, but are notlimited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl,n-butenyl, ethynyl, and tert-butyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or“cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon or bicyclicC₈-C₁₂ hydrocarbon that is completely saturated or that contains one ormore units of unsaturation, but which is not aromatic, that has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3-7 members. Suitablecycloaliphatic groups include, but are not limited to, cycloalkyl andcycloalkenyl groups. Specific examples include, but are not limited to,cyclohexyl, cyclopropenyl, and cyclobutyl.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic, or tricyclic ring systems inwhich one or more ring members are an independently selected heteroatom.In some embodiments, the “heterocycle”, “heterocyclyl”, or“heterocyclic” group has three to fourteen ring members in which one ormore ring members is a heteroatom independently selected from oxygen,sulfur, nitrogen, or phosphorus, and each ring in the system contains 3to 7 ring members.

Suitable heterocycles include, but are not limited to,3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl,2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl,4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g. cycloaliphatic and heterocycles), can be linearlyfused, bridged, or spirocyclic.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus, (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl or alkoxy, as the case may be, substituted with oneor more halogen atoms. The terms “halogen”, “halo”, and “hal” mean F,Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,or tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”. Suitable heteroaryl rings include, but arenot limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl,1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired reactive sites in a multifunctional compound. In certainembodiments, a protecting group has one or more, or preferably all, ofthe following characteristics: a) is added selectively to a functionalgroup in good yield to give a protected substrate that is b) stable toreactions occurring at one or more of the other reactive sites; and c)is selectively removable in good yield by reagents that do not attackthe regenerated, deprotected functional group. Exemplary protectinggroups are detailed in Greene, T. W., Wuts, P. G in “Protective Groupsin Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999(and other editions of the book), the entire contents of which arehereby incorporated by reference. The term “nitrogen protecting group”,as used herein, refers to an agents used to temporarily block one ormore desired nitrogen reactive sites in a multifunctional compound.Preferred nitrogen protecting groups also possess the characteristicsexemplified above, and certain exemplary nitrogen protecting groups arealso detailed in Chapter 7 in Greene, T. W., Wuts, P. G in “ProtectiveGroups in Organic Synthesis”, Third Edition, John Wiley & Sons, NewYork: 1999, the entire contents of which are hereby incorporated byreference.

In some embodiments, one of more methylene units in an alkyl oraliphatic chain can be optionally replaced with another atom or group.Examples of such atoms or groups would include, but are not limited to,—NR—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR—, —C(═N—CN),—NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—, —OC(O)NR—, —NRSO₂NR—,—SO—, or —SO₂—, wherein R is defined herein.

Unless otherwise specified, the optional replacements form a chemicallystable compound. Optional replacements can occur both within the chainand at either end of the chain; i.e. both at the point of attachmentand/or also at the terminal end. Two optional replacements can also beadjacent to each other within a chain so long as it results in achemically stable compound. The optional replacements can alsocompletely replace all of the carbon atoms in a chain. For example, a C₃aliphatic can be optionally replaced by —NR—, —C(O)—, and —NR— to form—NRC(O)NR— (a urea).

Unless otherwise specified, if the replacement occurs at the terminalend, the replacement atom is bound to a hydrogen atom on the terminalend. For example, if a methylene unit of —CH₂CH₂CH₃ were optionallyreplaced with —O—, the resulting compound could be —OCH₂CH₃, —CH₂OCH₃,or —CH₂CH₂OH.

Unless otherwise indicated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Unless otherwise indicated, a substituent can freely rotate around anyrotatable bonds. For example, a substituent drawn as

also represents

Additionally, unless otherwise indicated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

It will also be appreciated that the compounds of the present inventioncan exist in free form for treatment, or where appropriate, as apharmaceutically acceptable salt, salts, or mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds. Acid addition saltscan be prepared by 1) reacting the purified compound in its free-basedform with a suitable organic or inorganic acid and 2) isolating the saltthus formed.

Examples of pharmaceutically acceptable, nontoxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate,heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oleate, oxalate, palmitate, palmoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate,salicylate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like. Saltsderived from appropriate bases include alkali metal, alkaline earthmetal, ammonium and N⁺ (C₁₋₄alkyl)₄ salts. This invention also envisionsthe quaternization of any basic nitrogen-containing groups of thecompounds disclosed herein. Water or oil-soluble or dispersible productsmay be obtained by such quaternization.

Base addition salts can be prepared by 1) reacting the purified compoundin its acid form with a suitable organic or inorganic base and 2)isolating the salt thus formed. Base addition salts include alkali oralkaline earth metal salts. Representative alkali or alkaline earthmetal salts include sodium, lithium, potassium, calcium, magnesium, andthe like. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable acid or base addition salts.

The following abbreviations are used:

-   LiHMDS Lithium Hexamethyldisilazide-   DCM dichloromethane-   EtOAc ethyl acetate-   DMSO dimethyl sulfoxide-   ATP adenosine triphosphate-   DTT dithiothreitol-   NMR nuclear magnetic resonance-   HPLC high performance liquid chromatography-   LCMS liquid chromatography-mass spectrometry-   TLC thin layer chromatography-   Rt retention time

One embodiment provides a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ht is

-   -   Ring D is a 4-7 membered monocyclic ring or 8-10 membered        bicyclic ring selected from a heterocyclyl or a carbocyclyl        ring; said heterocyclyl ring having 1-4 ring heteroatoms        selected from nitrogen, oxygen or sulfur, wherein each        substitutable ring carbon of Ring D is independently substituted        with oxo or —R⁵, and any substitutable ring nitrogen is        independently substituted with —R⁴;    -   X is sulfur, oxygen, or NR^(2′);    -   Y is nitrogen or CR²;    -   Z¹ and Z² are each independently N or CR⁹; provided that at        least one of Z¹ or Z² is N;    -   R^(X) is T¹-R³;    -   R^(Y) is T²-R¹⁰;    -   R² and R^(2′) are independently selected from —R or -T³-W—R⁶; or        R² and R^(2′) are taken together with their intervening atoms to        form a fused, 5-8 membered, unsaturated or partially        unsaturated, ring having 0-3 ring heteroatoms selected from        nitrogen, oxygen, or sulfur, wherein each substitutable carbon        on said fused ring formed by R² and R^(2′) is substituted with        halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and any substitutable        nitrogen on said ring formed by R² and R^(2′) is substituted        with R⁴;    -   each T, T¹ and T³ is independently a bond or a C₁₋₄ alkylidene        chain;    -   T² is independently a bond or a C₁₋₄ alkylidene chain wherein up        to three methylene units of the alkylidene chain are optionally        replaced by —O—, —C(═O)—, —S(O)—, —S(O)₂—, —S—, or —N(R⁴)—;    -   R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,        —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,        —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂R″, —N(R⁴)N(R⁴)₂,        —C(═NH)N(R⁴)₂, —C(═NH)—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,        —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;    -   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂        (optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷,        or two R⁴ on the same nitrogen are taken together to form a 3-8        membered heterocyclyl or heteroaryl ring;    -   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,        —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,        —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂R″,        —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,        —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;    -   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,        —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,        —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—,        —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,        —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—,        —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,        —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;    -   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,        —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O)—,        —C(R⁶)₂OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—,        —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,        —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;    -   each R⁶ is independently selected from hydrogen or C₁₋₄        aliphatic group optionally substituted with 0-3 J⁶; or two R⁶        groups on the same nitrogen atom are taken together with the        nitrogen atom to form a 4-6 membered heterocyclyl or heteroaryl        ring, wherein said heterocyclyl or heteroaryl ring is optionally        substituted with 0-4 J⁶;    -   each R⁷ is independently selected from hydrogen or R″; or two R⁷        on the same nitrogen are taken together with the nitrogen to        form a 4-8 membered heterocyclyl or heteroaryl ring, wherein        said heterocyclyl or heteroaryl ring is optionally substituted        with 0-4 J⁷;    -   each R⁹ is —R′, -halo, —OR′, —C(═O)R′, —CO₂R′, —COCOR′,        COCH₂COR′, —NO₂, —CN, —S(O)R′, —S(O)₂R′, —SR′, —N(R′)₂,        —CON(R′)₂, —SO₂N(R′)₂, —OC(═O)R′, —N(R′)COR′, —N(R′)CO₂(C₁₋₆        aliphatic), —N(R′)N(R′)₂, —N(R′)CON(R′)₂, —N(R′)SO₂N(R′)₂,        —N(R′)SO₂R′, —OC(═O)N(R′)₂, ═NN(R′)₂, ═N—OR′, or ═O;    -   each R¹⁰ is a 4-membered heterocyclic ring containing 1-2        heteroatoms selected from O, NR¹¹, and S; each R¹⁰ is optionally        substituted with 0-3 occurrences of J;    -   each R¹¹, is —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆        aliphatic), —CON(R⁷)₂, or —SO₂R⁷;    -   each R is independently selected from hydrogen or an optionally        substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a        heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring        having 4-10 ring atoms; each R is optionally substituted with        0-5 R⁹;    -   each R′ is independently hydrogen or a C₁₋₆ aliphatic group        optionally substituted with 0-4 J′; or two R′, together with the        atom(s) to which they are attached, form a 3-6 membered        carbocyclyl or heterocyclyl wherein said carbocyclyl or        heterocyclyl is optionally substituted with 0-4 J′;    -   each R″ is independently C₁₋₆ aliphatic optionally substituted        with 0-4 J″;    -   each J′ and J″ is independently NH₂, NH(C₁₋₄aliphatic),        N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic),        NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or        haloC₁₋₄aliphatic;    -   each J, J⁶, and J⁸ is independently -halo, —OR, oxo, C₁₋₆        aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R,        —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R,        —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, ═NN(R⁴)₂,        ═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or        —OC(═O)N(R⁷)₂;    -   2 J groups, 2 J⁶ groups, 2 J⁷ groups, or 2 J⁸ groups, on the        same atom or on different atoms, together with the atom(s) to        which they are bound, form a 3-8 membered saturated, partially        saturated, or unsaturated ring having 0-2 heteroatoms selected        from O, N, or S.

In some embodiments of this invention, Ht is

In some embodiments, Ht is

In other embodiments, Ht is

In another embodiment of this invention, X is S. In another embodiment,X is NR^(2′). In some embodiments, Y is N or CR². In other embodiments,Y is N. In yet other embodiments, Y is CR². In some embodiments, X is Sand Y is N. In other embodiments, X is S and Y is CR².

In some embodiments, T² is independently a bond or a C₁₋₄ alkylidenechain wherein up to three methylene units of the alkylidene chain areoptionally replaced by —O—, —C(═O)—, —S(O)—, —S(O)₂—, —S—, or —N(R⁴) —;In some embodiments, said optional replacements in the methylene unitsof T are selected from —CO₂—, —COCO—, —COCH₂CO—, —S(O)—, —S(O)₂—, —S—,—N(R⁴)—, —CON(R⁷)—, —SO₂N(R⁷) —, —OC(═O)—, —N(R⁷)CO—, —N(R⁷)CO₂—,—N(R⁴)N(R⁴)—, —N(R⁷)CON(R⁷)—, —N(R⁷)SO₂N(R⁷)—, —N(R⁴)SO₂—, or—OC(═O)N(R⁷⁾—.

In some embodiments of this invention, Z¹ and Z² are both nitrogen. Inother embodiments, Z¹ is CR⁹ and Z² is nitrogen. In yet otherembodiments, Z¹ is nitrogen and Z² is CH.

In some embodiments of this invention, R^(2′) is hydrogen or methyl. Insome embodiments, R^(2′) is hydrogen.

In other embodiments, R² is T3-W—R⁶ or R; wherein W is —C(R⁶)₂O—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O) —, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁶)—, and R is an optionally substitutedgroup selected from C₁₋₆ aliphatic or phenyl. In yet other embodiments,R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group. In some embodiments, R² ishydrogen or a substituted or unsubstituted group selected from aryl or aC₁₋₆ aliphatic group.

In some embodiments of this invention, R² and R^(2′) are taken togetherwith their intervening atoms to form a substituted or unsubstitutedbenzo, pyrido, pyrimido or partially unsaturated 6-membered carbocycloring. In other embodiments, R² and R^(2′) are taken together with theirintervening atoms to form a substituted or unsubstituted benzo or pyridoring. In some embodiments, said benzo or pyrido ring is substituted with1-2 halo substituents.

In another aspect of this invention, R^(X) is hydrogen, C₁₋₄aliphatic,or halo. In some embodiments, R^(X) is hydrogen, fluoro, methyl, ethyl,cyclopropyl, or isopropyl. In other embodiments, R^(X) is hydrogen.

In another aspect of this invention, R^(Y) is represented by formulaii-a:

In yet another aspect of this invention, R^(Y) is T²-R¹⁰ wherein T² is abond. In some embodiments, R¹⁰ is an optionally substituted azetidine.

In yet another aspect of this invention, R^(Y) is represented by formulai:

In yet another aspect of this invention, R^(Y) is represented by formulaiii:

In some embodiments, R¹¹ is H.

In one aspect of this invention, Ring D is an optionally substitutedring selected from piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, or isoquinolinyl. Insome embodiments, Ring D is optionally substituted tetrahydronaphthyl,benzodioxinyl, indanyl, indolinyl, or isoquinolinyl. In someembodiments, Ring D is 5-8 membered cycloalkyl. In some embodiments,Ring D is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments,Ring D is cyclohexyl.

In another aspect of this invention, R¹ is -halo, an optionallysubstituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶,—SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. Insome embodiments, R¹ is -halo, a C₁₋₆ haloaliphatic group, an optionallysubstituted C₁₋₆ aliphatic group, phenyl, or —CN. In other embodiments,R¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN.

In some embodiments, each J, J⁶, and J⁸ is independently -halo, —OR,oxo, C₁₋₆ aliphatic, —C(═O) R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN,—S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R,—N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, ═NN(R⁴)₂, ═N—OR,—N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O) N(R⁷)₂;

In some embodiments, each J⁷ is independently -halo, —OR, oxo, C₁₋₆aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R,—SR, —N(R¹²)₂, —CON(R¹²)₂, —SO₂N(R¹²)₂, —OC(═O)R, —N(R¹²)COR, —N(R¹²)CO₂(C₁₋₆ aliphatic), —N(R¹³)N(R¹²)₂, ═NN(R¹²)₂, ═N—OR, —N(R¹²)CON(R¹²)₂,—N(R¹²)SO₂N(R¹²)₂, —N(R¹²)SO₂R, or —OC(═O)N(R¹²)₂; wherein R¹² isindependently selected from hydrogen or R″; or two R¹² on the samenitrogen are taken together with the nitrogen to form a 4-8 memberedheterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroarylring is optionally substituted with 0-4 J″.

In some embodiments, two R⁴ on the same nitrogen are taken together toform a 3-8 membered heterocyclyl or heteroaryl ring. In otherembodiments, each R⁴ is independently selected from —R⁷, —COR₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷. In someembodiments, said C₁₋₆ aliphatic is optionally substituted with 0-2 J″.In some embodiments, said C₁₋₆ aliphatic is unsubstituted.

In some embodiments, each R⁶ is independently selected from hydrogen orC₁₋₄ aliphatic group optionally substituted with 0-3 J⁶; or two R⁶groups on the same nitrogen atom are taken together with the nitrogenatom to form a 4-6 membered heterocyclyl or heteroaryl ring, whereinsaid heterocyclyl or heteroaryl ring is optionally substituted with 0-4J⁶. In some embodiments, two R⁶ groups on the same nitrogen atom aretaken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroarylring is optionally substituted with 0-4 J⁶.

One embodiment of this invention is represented by formula Ia:

Another embodiment of this invention is represented by formula Ib:

Another embodiment of this invention is represented by formula Ic:

Another embodiment of this invention is represented by formula Id:

Another embodiment of this invention is represented by formula Ie:

Another embodiment of this invention is represented by formula If:

wherein R² and R^(2′) are taken together with their intervening atoms toform a substituted or unsubstituted benzo or pyrido ring.

In some embodiments, the variables are as depicted in the compounds ofTable 1.

In some embodiments, the compounds of this invention are as representedin Table 1:

TABLE 1

I-1

I-2

I-3General Synthetic Methodology

The compounds of this invention may be prepared in general by methodssuch as those depicted in the general schemes below, and the preparativeexamples that follow. Unless otherwise indicated, all variables in thefollowing schemes are as defined herein.

Scheme 1 above shows a general synthetic route that is used forpreparing the compounds 5. Compounds of formula 5 can be prepared fromintermediate 3. The formation of intermediate 3 is achieved by reactingdiethyl malonate with the corresponding amidine in the presence of EtONaas a base in refluxing ethanol. Then the crude is treated with POCl₃ toyield dichloropyrimidine intermediate 3. Then the dichloropyrimidineintermediate is sequentially treated with heterocyclic amines andazetidine derivatives to yield final compounds 5. These two reactionssequence are amenable to a variety of heterocyclic amines andsubstituted azetidines.

The present invention provides compounds and compositions that areuseful as inhibitors of protein kinases. In some embodiments, theprotein kinases are GSK-3 kinases.

As inhibitors of protein kinases, the compounds and compositions of thisinvention are particularly useful for treating or lessening the severityof a disease, condition, or disorder where a protein kinase isimplicated in the disease, condition, or disorder. In one aspect, thepresent invention provides a method for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease state. In another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where inhibition of enzymatic activityis implicated in the treatment of the disease. In another aspect, thisinvention provides a method for treating or lessening the severity of adisease, condition, or disorder with compounds that inhibit enzymaticactivity by binding to the protein kinase. Another aspect provides amethod for treating or lessening the severity of a kinase disease,condition, or disorder by inhibiting enzymatic activity of the kinasewith a protein kinase inhibitor.

In some embodiments, said protein kinase inhibitor is GSK-3.

As inhibitors of protein kinases, the compounds and compositions of thisinvention are also useful in biological samples. One aspect of theinvention relates to inhibiting protein kinase activity in a biologicalsample, which method comprises contacting said biological sample with acompound of formula I or a composition comprising said compound. Theterm “biological sample”, as used herein, means an in vitro or an exvivo sample, including, cell cultures or extracts thereof; biopsiedmaterial obtained from a mammal or extracts thereof; and blood, saliva,urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

Another aspect of this invention relates to the study of protein kinasesin biological and pathological phenomena; the study of intracellularsignal transduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the kinase activity or ATPaseactivity of the activated kinase. Alternate in vitro assays quantitatethe ability of the inhibitor to bind to the protein kinase and may bemeasured either by radiolabelling the inhibitor prior to binding,isolating the inhibitor/kinase complex and determining the amount ofradiolabel bound, or by running a competition experiment where newinhibitors are incubated with the kinase bound to known radioligands.

Another aspect of this invention provides compounds that are useful forthe treatment of diseases, disorders, and conditions including, but notlimited to, autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases,immunodeficiency disorders, immunomodulatory or immunosuppressivedisorder, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, neurotrophic factor, cardiovasculardiseases, hormone related diseases, diabetes, allergies, asthma, andAlzheimer's disease. Another aspect of this invention provides compoundsthat are inhibitors of protein kinases, and thus are useful for thetreatment of the diseases, disorders, and conditions, along with otheruses described herein.

Another aspect provides pharmaceutically acceptable compositionscomprising any of the compounds described herein and optionallycomprising a pharmaceutically acceptable carrier, adjuvant or vehicle.In certain embodiments, these compositions optionally further compriseone or more additional therapeutic agents.

One aspect of this invention provides a method for the treatment orlessening the severity of a disease, disorder, or condition selectedfrom an autoimmune disease, an inflammatory disease, a proliferative orhyperproliferative disease, such as cancer, an immunologically-mediateddisease, an immunodeficiency disorders, a bone disease, a metabolicdisease, a neurological or neurodegenerative disease, a cardiovasculardisease, allergies, diabetes, asthma, Alzheimer's disease, or a hormonerelated disease, comprising administering an effective amount of acompound, or a pharmaceutically acceptable composition comprising acompound, to a subject in need thereof.

The term “cancer” includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions. In some embodiments, the cancer is selectedfrom colorectal, thyroid, or breast cancer.

The term “Aurora-mediated condition” or “Aurora-mediated disease” asused herein means any disease or other deleterious condition in whichAurora (Aurora A, Aurora B, and Aurora C) is known to play a role. Suchconditions include, without limitation, cancer such as colorectal,thyroid, and breast cancer; and myeloproliferative disorders, such aspolycythemia vera, thrombocythemia, myeloid metaplasia withmyelofibrosis, chronic myelogenous leukaemia (CML), chronicmyelomonocytic leukemia, hypereosinophilic syndrome, juvenilemyelomonocytic leukemia, and systemic mast cell disease.

In certain embodiments, an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective inorder to treat said disease. The compounds and compositions, accordingto the method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of said disease. In some embodiments, saiddisease is chosen from allergic or type I hypersensitivity reactions,asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson'sdisease, AIDS-associated dementia, bipolar disorder, amyotrophic lateralsclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS),schizophrenia, leukocytopenia, cardiomyocyte hypertrophy,reperfusion/ischemia, stroke, baldness, transplant rejection, graftversus host disease, rheumatoid arthritis, and solid and hematologicmalignancies. In some embodiments, said disease is chosen from diabetes,bipolar disorder, schizophrenia, stroke, Huntington's disease,leukocytopenia and cardiomyocyte hypertrophy.

In other embodiments of this invention, said disease is a protein-kinasemediated condition. In some embodiments, said protein kinase in GSK-3.

The term “protein kinase-mediated condition”, as used herein means anydisease or other deleterious condition in which a protein kinase plays arole. Such conditions include, without limitation, autoimmune diseases,inflammatory diseases, proliferative and hyperproliferative diseases,immunologically-mediated diseases, immuno-deficiency disorders,immunomodulatory or immunosuppressive disorder, bone diseases, metabolicdiseases, neurological and neurodegenerative diseases, cardiovasculardiseases, hormone related diseases, diabetes, allergies, asthma, andAlzheimer's disease.

The term “GSK-3-mediated condition”, as used herein means any disease orother deleterious condition in which GSK-3 plays a role. Such conditionsinclude, without limitation, diabetes, Alzheimer's disease, Huntington'sdisease, Parkinson's disease, AIDS-associated dementia, bipolardisorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease),multiple sclerosis (MS), schizophrenia, leukocytopenia, cardiomyocytehypertrophy, stroke, and rheumatoid arthritis.

In some embodiments, the compounds are used to treat diabetes bypromoting beta cell regeneration.

In other embodiments, the compounds are used to treat stroke recovery.In some cases, the compounds are used in post-stroke administration. Thelength of treatment can range from 1 month to one year.

In yet other embodiments, the compounds are used to treat osteoporosisby osteoblastogenesis.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable salt or pharmaceutically acceptablederivative thereof.

It should be understood that this invention includesmixtures/combinations of different pharmaceutically acceptable salts andalso mixtures/combinations of compounds in free form andpharmaceutically acceptable salts.

As described herein, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The protein kinase inhibitors or pharmaceutical salts thereof may beformulated into pharmaceutical compositions for administration toanimals or humans. These pharmaceutical compositions, which comprise anamount of the protein inhibitor effective to treat or prevent a proteinkinase-mediated condition and a pharmaceutically acceptable carrier, areanother embodiment of the present invention. In some embodiments, saidprotein kinase-mediated condition is a GSK-3-mediated condition. In someembodiments, a GSK-3-mediated condition.

The exact amount of compound required for treatment will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable ester, salt of an ester or other derivativeof a compound of this invention which, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favoured derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated, the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

According to another embodiment, the invention provides methods fortreating or preventing a protein kinase-mediated condition (in someembodiments, a GSK-3-mediated condition) comprising the step ofadministering to a patient one of the above-described pharmaceuticalcompositions. The term “patient”, as used herein, means an animal,preferably a human.

In some embodiments, that method is used to treat or prevent a conditionselected from cancers such as cancers of the breast, colon, prostate,skin, pancreas, brain, genitourinary tract, lymphatic system, stomach,larynx and lung, including lung adenocarcinoma and small cell lungcancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly,Alzheimer's disease, cystic fibrosis, and viral disease, or any specificdisease described above.

In other embodiments, that method is used to treat or prevent acondition selected from diabetes, Alzheimer's disease, Huntington'sdisease, Parkinson's disease, AIDS-associated dementia, bipolardisorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease),multiple sclerosis (MS), schizophrenia, leukocytopenia, cardiomyocytehypertrophy, stroke, or rheumatoid arthritis.

In some embodiments, that method is used to treat diabetes by promotingbeta cell regeneration.

In other embodiments, that method is used to treat stroke recovery. Insome cases, the compositions are used in post-stroke administration. Thelength of treatment can range from 1 month to one year.

In yet other embodiments, the compositions are used to treatosteoporosis by osteoblastogenesis.

Another aspect of the invention relates to inhibiting protein kinaseactivity in a patient, which method comprises administering to thepatient a compound of formula I or a composition comprising saidcompound.

Depending upon the particular protein kinase-mediated conditions to betreated or prevented, additional drugs, which are normally administeredto treat or prevent that condition, may be administered together withthe inhibitors of this invention. For example, chemotherapeutic agentsor other anti-proliferative agents may be combined with the proteinkinase inhibitors of this invention to treat proliferative diseases.

Those additional agents may be administered separately, as part of amultiple dosage regimen, from the protein kinase inhibitor-containingcompound or composition. Alternatively, those agents may be part of asingle dosage form, mixed together with the protein kinase inhibitor ina single composition.

In some embodiments, said protein kinase inhibitor is a GSK-3 kinaseinhibitor.

This invention may also be used in methods other than those involvingadministration to a patient.

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art. Those compounds may be analyzed byknown methods, including but not limited to LCMS (liquid chromatographymass spectrometry) and NMR (nuclear magnetic resonance). Compounds ofthis invention may be also tested according to these examples. It shouldbe understood that the specific conditions shown below are onlyexamples, and are not meant to limit the scope of the conditions thatcan be used for making, analyzing, or testing the compounds of thisinvention. Instead, this invention also includes conditions known tothose skilled in that art for making, analyzing, and testing thecompounds of this invention.

EXAMPLES

As used herein, the term “Rt(min)” refers to the HPLC or LCMS retentiontime, in minutes, associated with the compound.

Unless otherwise indicated, the HPLC method utilized to obtain thereported retention time is as follows:

-   -   Column: ACE C8 column, 4.6×150 mm    -   Gradient: 0-100% acetonitrile+methanol 60:40 (20 mM Tris        phosphate)    -   Flow rate: 1.5 mL/minute    -   Detection: 225 nm.

Mass spec. samples were analyzed on a MicroMass Quattro Micro massspectrometer operated in single MS mode with electrospray ionization.Samples were introduced into the mass spectrometer using chromatography.Mobile phase for all mass spec. analyses consisted of 10 mM pH 7ammonium acetate and a 1:1 acetonitrile-methanol mixture, columngradient conditions are 5%-100% acetonitrile-methanol over 3.5 minsgradient time and 5 mins run time on an ACE C8 3.0×75 mm column. Flowrate is 1.2 ml/min.

¹H-NMR spectra were recorded at 400 MHz using a Bruker DPX 400instrument. The following compounds of formula I were prepared andanalyzed as follows.

Intermediate 1

Cyclohexanecarboximidamide hydrochloride

Hydrogen chloride gas was bubbled through a solution ofcyclohexanecarbonitrile (60 g, 550 mmol) in a mixture of MeOH (33 ml)and Et₂O (150 ml) with stirring at 0° C. After bubbling for 1 h theflask was removed to the fridge where it remained overnight. The RM wasthen diluted with Et₂O and the resulting solid filtered. The crude solidwas dissolved in an ethanol (400 mL) and 2N ammonia in ethanol (100 mL)mixture. Ammonia gas was bubbled through this suspension for 1 h beforethe reaction mixture was removed to the fridge overnight. The reactionmixture was filtered and the sticky solid washed into a flask withmethanol. The mixture was concentrated in-vacuo, Et₂O added and thesolid filtered. The solid was redissolved in methanol and concentrateduntil a solid began to precipitate at which stage Et₂O was added. Thesolid was then filtered and placed on the high-vacuum overnight to givethe title compound as a solid (87.8 g, 98%). ¹H NMR: (DMSO) 1.00-1.88(10H, m), 2.35-2.57 (1H, m), 8.86 (1H, s), 9.02 (1H, s).

Intermediate 2

2-cyclohexylpyrimidine-4,6-diol

A solution of sodium ethoxide in ethanol [previously prepared bydissolving sodium (2.12 g, 92.2 mmol) in ethanol (200 mL)] was treatedwith diethyl malonate (6.1 mL, 40.2 mmol) with stirring at ambienttemperature. A solution of cyclohexanecarboximidamide hydrochloride (5g, 31 mmol) in ethanol (100 mL) was then added dropwise with stirring atroom temperature. On completion of addition the reaction mixture washeated at reflux for 8 h and allowed to stand overnight. The reactionmixture was concentrated in vacuo, water added and the pH adjusted to pH7-8 using 2N HCl. The resulting solid formed was filtered and washedwith diethyl ether to give the title compound as a solid (5.53 g, 93%).MS (ES+) m/e=195. ¹H NMR: (DMSO) 1.09-1.81 (10H, m), 2.40-2.53 (1H, m),5.09 (1H, s), 11.61 (2H, brs).

Intermediate 3

4,6-Dichloro-2-cyclohexylpyrimidine

A mixture containing 2-cyclohexylpyrimidine-4,6-diol (5.53 g, 28.5 mmol)and phosphoryl chloride (70 mL, 751 mmol) was heated at reflux for 3 hbefore being cooled to room temperature and concentrated in vacuo. Thesemi-solid formed was then treated with ice-water, sNaHCO₃, extractedwith Et₂O and dried (Na₂SO₄) and concentrated in-vacuo. The resultingresidue was purified by column chromatography (eluting withEtOAc/Petrol, 1/9) to give the title compound as an oil (5.74 g, 87%).MS (ES+) m/e=231. ¹H NMR: (DMSO) 1.15-2.00 (10H, m), 2.70-2.84 (1H, m),7.86 (1H, s).

Intermediate 4

N-(6-chloro-2-cyclohexylpyrimidin-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine

A mixture cooled to −60° C. containing4,6-dichloro-2-cyclohexylpyrimidine (505 mg, 2.19 mmol),5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (400 mg, 2.63 mmol) and THF(20 mL) was treated drop wise with a 1M solution of lithiumbis(trimethylsilyl)amide in THF (5.46 mL, 5.46 mmol). The reactionmixture was then allowed to warm to 0° C. over 1 h before water wasadded. The reaction mixture partitioned between water and EtOAc, washedwith sat. NaCl solution and dried (Na₂SO₄) and concentrated in-vacuo.The resulting residue was purified by column chromatography (elutingwith MeOH/DCM, 5/95) to give the title compound as a solid (380 mg,50%). MS (ES+) m/e=347. ¹H NMR: (DMSO) 1.10-1.96 (10H, m), 2.56-2.69(1H, m), 7.65 (1H, brs), 8.27-8.39 (1H, m), 8.58 (1H, s), 10.72 (1H, s),13.34 (1H, s).

Example 1

N-(6-(azetidin-1-yl)-2-cyclohexylpyrimidin-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine

A mixture containingN-(6-chloro-2-cyclohexylpyrimidin-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine(78 mg, 0.22 mmol), N, N-diisopropylethylamine (158 μL, 0.91 mmol),azetidine (45 μL, 0.67 mmol) and n-butanol (6 mL) was heated at 125° C.for 20 min in the microwave. The reaction mixture was cooled to roomtemperature and the resulting solid was filtered and the solid washedwith Et₂O, sNH₄Cl and Et₂O. The resulting solid was air dried to givethe title compound as a white solid (48 mg, 58%). MS (ES+) m/e=368. ¹HNMR: (DMSO) 1.08-1.92 (10H, m), 2.26-2.58 (3H, m), 3.89-4.06 (4H, m),6.50 (1H, brs), 8.32-8.62 (2H, m), 9.79 (1H, s), 13.03 (1H, s)

The follow compounds were prepared according to the method used toprepare compound I-1.

LCMS Compound # LCMS Rt (min) NMR

I-1 368.00 3.92 (400 MHz, DMSO) 1.08-1.92 (10H, m), 2.26-2.58 (3H, m),3.89-4.06 (4H, m), 6.50 (1H, brs), 8.32-8.62 (2H, m), 9.79 (1H, s),13.03 (1H, s).

I-2 313.0 3.72 (400 MHz, DMSO) 1.13-1.88 (10H, m), 2.13-2.60 (6H, m),3.86-3.94 (4H, m), 5.91 (1H, brs), 6.12 (1H, brs), 8.98 (1H, brs), 11.81(1H, brs).

I-3 367.0 3.97 (400 MHz, DMSO) 1.12-1.89 (10H, m), 2.26-2.54 (3H, m),3.91-4.00 (4H, m), 6.55 (1H, s), 7.17-7.29 (1H, m), 7.38-7.46 (1H, m),7.84-7.96 (1H, m), 9.57 (1H, s), 12.44 (1H, s).

Example 2

The overall synthetic scheme for the synthesis of5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (5a) is depicted below.

2-chloro-5-fluoronicotinic acid (6a)

To a round-bottomed flask under a N₂ atmosphere were added degassed DMF(270 mL), Pd(OAc)₂ (0.05 eq, 2.7 g, 11.9 mmol), PPh₃ (0.1 eq, 6.2 g,23.8 mmol) and degassed Et₃N (6 eq, 200 mL, 1428.6 mmol). The mixturewas stirred 20 minutes then HCOOH (3 eq, 28 mL, 714.3 mmol) was addedfollowed after 5 minutes by 2,6-dichloro-5-fluoronicotinic acid (50 g,238.1 mmol) and the mixture was stirred at 50° C. The reaction wasfollowed by analysis (1H NMR) of a worked-up aliquot. When all startingmaterial was consumed (24 h), the mixture was cooled to 0° C. and water(500 mL) was added. After 20 minutes, The mixture was filtered through apad of Celite that was rinsed with water. The mixture was basified to pH9 with 30% aq. NaOH and washed with EtOAc (2×). HCl (12 N) was addedslowly to pH 1 and the solution was saturated with NaCl. The mixture wasextracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated under reduced pressure togive 37 g (88%) of a beige solid used in the next step without furtherpurification.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.16 (dd, 1H); 8.58 (d, 1H)

2-Chloro-5-fluoronicotinamide (3a)

To a solution of 2-chloro-5-fluoronicotinic acid 6a (50 g, 285 mmol) andDMF (2 mL, 28 mmol) in DCM (400 mL) at 0° C. was added oxalyl chloride(64 mL, 741 mmol) dropwise. The reaction mixture was stirred at roomtemperature overnight and concentrated in vacuo. The resulting yellowliquid was dissolved in 1,4-dioxane (600 mL), cooled at 0° C. and NH₃(g)was bubbled through the solution for 30 minutes. The mixture was stirredat room temperature overnight. The resulting mixture was filtered andthe filtrate was concentrated to give compound 3a (44 g, 89%) as a beigesolid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.84 (s, 1H), 7.96 (dd, 1H), 8.09(s, 1H), 8.49 (d, 1H).

2-Chloro-5-fluoronicotinonitrile (4a)

A suspension of crude compound 3a (65 g, 372.4 mmol) and Et₃N (114 mL,819.2 mmol) in DCM (700 mL) was cooled to 0° C. and TFAA (57 mL, 409.6mmol) and was added dropwise. The resulting yellow solution was stirredfor 90 minutes at 0° C., diluted with DCM, washed with sat. aq. NaHCO₃and brine, and dried (Na₂SO₄). The mixture was filtered andconcentrated. Kugel Rohr distillation of the residue (˜70° C./1 mbar)gave 50 g (86%) of compound 4a as a beige solid. Compound 4a can also bepurified by column chromatography (SiO₂, 8:1 heptane: EtOAc). ¹H NMR(CDCl₃, 300 MHz): δ 7.78 (dd, 1H); 8.49 (d, 1H).

5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (5a)

To a solution of compound 4a (50 g, 321.7 mmol) in 1-butanol (1 L) wasadded hydrazine monohydrate (150 mL, 3.2 mol), and the mixture wasrefluxed for 4 h. The mixture was cooled to room temperature andconcentrated. The precipitate was successively washed on filter withwater (2×) and Et₂O (2×) and dried in vacuo overnight to give compound5a (44 g, 88%) as a yellow solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 5.53 (s,2H); 7.94 (dd, 1H); 8.35 (dd, 1H); 12.02 (s, 1H).

Example 3 GSK-3 Inhibition Assay

Compounds of the present invention were screened for their ability toinhibit GSK-3β (AA 1-420) activity using a standard coupled enzymesystem (Fox et al., Protein Sci. 1998, 7, 2249). Reactions were carriedout in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mMNaCl, 300 μM NADH, 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 20 μM ATP (Sigma Chemicals, St Louis,Mo.) and 300 μM peptide (American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofthe present invention. The assay stock buffer solution (175 μl) wasincubated in a 96 well plate with 5 μl of the test compound of thepresent invention at final concentrations spanning 0.002 μM to 30 μM at30° C. for 10 min. Typically, a 12-point titration was conducted bypreparing serial dilutions (from 10 mM compound stocks) with DMSO of thetest compounds of the present invention in daughter plates. The reactionwas initiated by the addition of 20 μl of ATP (final concentration 20μM). Rates of reaction were obtained using a Molecular DevicesSpectramax plate reader (Sunnyvale, Calif.) over 10 min at 30° C. TheK_(i) values were determined from the rate data as a function ofinhibitor concentration. Compounds I-1 and I-2 were found to inhibitGSK-3 at a Ki value of <50 nM. Compound I-3 was found to inhibit GSK-3at a Ki value between 50 and 100 nM.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize or encompass the compounds, methods, andprocesses of this invention. Therefore, it will be appreciated that thescope of this invention is to be defined by the appended claims.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ht is

Ring D is a 4-7 membered monocyclic carbocyclyl ring or 8-10 memberedbicyclic carbocyclyl ring, wherein each substitutable ring carbon ofRing D is independently substituted with oxo or —R⁵; X is sulfur,oxygen, or NR^(2′); Y is nitrogen or CR²; Z¹ and Z² are eachindependently N; R^(X) is T¹-R³; R^(Y) is T²-R¹⁰; R² and R^(2′) areindependently selected from —R or -T³-W—R⁶; or R² and R^(2′) are takentogether with their intervening atoms to form a fused, 5-8 membered,unsaturated or partially unsaturated, ring having 0-3 ring heteroatomsselected from nitrogen, oxygen, or sulfur, wherein each substitutablecarbon on said fused ring formed by R² and R^(2′) is substituted withhalo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and any substitutable nitrogen onsaid ring formed by R² and R^(2′) is substituted with R⁴; each T¹ and T³is independently a bond or a C₁₋₄ alkylidene chain; T² is independentlya bond or a C₁₋₄ alkylidene chain wherein up to three methylene units ofthe alkylidene chain are optionally replaced by —O—, —C(═O)—, —S(O)—,—S(O)₂—, —S—, or —N(R⁴)—; R³ is selected from —R, -halo, —OR, —C(═O)R,—CO₂R, —COLOR, —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂,—CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂R″, —N(R⁴)N(R⁴)₂,—C(═NH)N(R⁴)₂, —C(═NH)—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R,or —OC(═O)N(R)₂; each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, ortwo R⁴ on the same nitrogen are taken together to form a 3-8 memberedheterocyclyl or heteroaryl ring; each R⁵ is independently selected from—R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂R″,—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—,—SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—,—N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—,—OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—,—C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,or —C(R⁶)₂N(R⁶)CON(R⁶)—; W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—,—C(R⁶)₂OC(O)—, —C(R⁶)₂OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—,—C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—; each R⁶ is independently selectedfrom hydrogen or C₁₋₄ aliphatic group optionally substituted with 0-3J⁶; or two R⁶ groups on the same nitrogen atom are taken together withthe nitrogen atom to form a 4-6 membered heterocyclyl or heteroarylring, wherein said heterocyclyl or heteroaryl ring is optionallysubstituted with 0-4 J6; each R⁷ is independently selected from hydrogenor R″; or two R⁷ on the same nitrogen are taken together with thenitrogen to form a 4-8 membered heterocyclyl or heteroaryl ring, whereinsaid heterocyclyl or heteroaryl ring is optionally substituted with 0-4J⁷; each R⁹ is —R′, -halo, —OR′, —C(═O)R′, —CO₂R′, —COCOR′, COCH₂COR′,—NO₂, —CN, —S(O)R′, —S(O)₂R′, —SR′, —N(R′)₂, —CON(R)₂, —SO₂N(R′)₂,—OC(═O)R′, —N(R′)COR′, —N(R′)CO₂(C₁₋₆ aliphatic), —N(R′)N(R′)₂,—N(R′)CON(R′)₂, —N(R′)SO₂N(R′)₂, —N(R′)SO₂R′, —OC(═O)N(R′)₂, ═NN(R′)₂,═N—OR′, or ═O; each R¹⁰ is a 4-membered heterocyclic ring containing 1-2heteroatoms selected from O, NR¹¹, and S; each R¹⁰ is optionallysubstituted with 0-3 occurrences of J; each R¹¹ is —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷; eachR is independently selected from hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms; each Ris optionally substituted with 0-5 R⁹; each R′ is independently hydrogenor a C₁₋₆ aliphatic group optionally substituted with 0-4 J′; or two R′,together with the atom(s) to which they are attached, form a 3-6membered carbocyclyl or heterocyclyl wherein said carbocyclyl orheterocyclyl is optionally substituted with 0-4 J′; each R″ isindependently C₁₋₆ aliphatic optionally substituted with 0-4 J″; each J′and J″ is independently NH₂, NH(C₁₋₄-aliphatic), N(C₁₋₄-aliphatic)₂,halogen, C₁₋₄-aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H,CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic; each J,J⁶, and J⁸ is independently -halo, —OR, oxo, C₁₋₆ aliphatic, —C(═O)R,—CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂,—CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, ═NN(R⁴)₂, ═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R)₂; each J⁷ is independently -halo, —OR, oxo,C₁₋₆ aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R,—S(O)₂R, —SR, —N(R¹²)₂, —CON(R¹²)₂, —SO₂N(R¹²)₂, —OC(═O)R, —N(R¹²)COR,—N(R¹²)CO₂(C₁₋₆ aliphatic), —N(R¹²)N(R¹²)₂, ═NN(R¹²)₂, ═N—OR,—N(R¹²)CON(R¹²)₂, —N(R¹²)SO₂N(R¹²)₂, —N(R¹²)SO₂R, or —OC(═O)N(R¹²)₂; or2 J groups, 2 J⁶ groups, 2 J⁷ groups, or 2 J⁸ groups, on the same atomor on different atoms, together with the atom(s) to which they arebound, form a 3-8 membered saturated, partially saturated, orunsaturated ring having 0-2 heteroatoms selected from 0, N, or S; R¹² isindependently selected from hydrogen or R″; or two R¹² on the samenitrogen are taken together with the nitrogen to form a 4-8 memberedheterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroarylring is optionally substituted with 0-4 J″.
 2. The compound according toclaim 1 wherein Ht is


3. The compound according to claim 1 wherein Ht is


4. The compound according to claim 3, wherein X is NR^(2′).
 5. Thecompound according to claim 3, wherein X is sulfur and Y is CR².
 6. Thecompound according to claim 2, wherein R^(2′) is hydrogen or methyl. 7.The compound according to claim 6, wherein R^(2′) is hydrogen.
 8. Thecompound according to claim 6, wherein R² is T³-W—R⁶ or R, wherein W is—C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁶)—, and R is an optionally substitutedgroup selected from C₁₋₆ aliphatic or phenyl.
 9. The compound accordingto claim 6, wherein R² is hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.
 10. Thecompound according to claim 9, wherein R² is hydrogen or a substitutedor unsubstituted group selected from aryl or a C₁₋₆ aliphatic group. 11.The compound according to claim 2, wherein R² and R^(2′) are takentogether with their intervening atoms to form a substituted orunsubstituted benzo, pyrido, pyrimido or partially unsaturated6-membered carbocyclo ring.
 12. The compound according to claim 11,wherein R² and R^(2′) are taken together with their intervening atoms toform a substituted or unsubstituted benzo or pyrido ring.
 13. Thecompound according to claim 12, wherein said benzo or pyrido ring issubstituted with 1-2 halo substituents.
 14. The compound according toclaim 2, wherein R^(X) is hydrogen, C₁₋₄aliphatic, or halo.
 15. Thecompound according to claim 14, wherein R^(X) is hydrogen, methyl,ethyl, cyclopropyl, or isopropyl.
 16. The compound according to claim15, wherein R^(X) is hydrogen.
 17. The compound according to claim 2,wherein R^(Y) is represented by formula ii-a:


18. The compound according to claim 2, wherein R^(Y) is T²-R¹⁰ whereinT² is a bond.
 19. The compound according to claim 11, wherein R¹⁰ is anoptionally substituted azetidine.
 20. The compound according to claim19, wherein R^(Y) is represented by formula i:


21. The compound according to claim 19, wherein R^(Y) is represented byformula iii:


22. The compound according to claim 2, wherein Ring D is an optionallysubstituted ring selected from piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, or2,3-dihydro-1H-indolyl.
 23. The compound according to claim 2, whereinRing D is optionally substituted tetrahydronaphthyl, benzodioxinyl,indanyl, or indolinyl.
 24. The compound according to claim 2, whereinRing D is cyclohexyl.
 25. The compound of claim 1 selected from thefollowing:


26. A composition comprising a compound according to claim 1, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 27. A methodof inhibiting GSK-3 activity in an ex vivo or in vitro biological samplewith a compound according to claim
 1. 28. A method of treating orlessening the severity of a disease or condition selected from diabetes,Alzheimer's disease, bipolar disorder, schizophrenia, and stroke,comprising the step of administering to said patient a compoundaccording to claim
 1. 29. The method of claim 28, wherein said diseaseis stroke.
 30. The method of claim 28, wherein said disease is diabetes.31. The method of claim 28, wherein said disease is schizophrenia. 32.The method of claim 28, wherein said disease is bipolar disorder.
 33. Amethod of treating or lessening the severity of a disease or conditionselected from diabetes or stroke recovery comprising the step ofadministering to said patient a compound according to claim 1.